Medical Reviews

Frilling A1, Modlin IM2, Kidd M3, Russell C4, Breitenstein S5, Salem R6, Kwekkeboom D7, Lau WY8, Klersy C9, Vilgrain V10, Davidson B4, Siegler M11, Caplin M12, Solcia E9, Schilsky R13; Working Group on Neuroendocrine Liver Metastases.

Lancet Oncol. 2014 Jan;15(1):e8-e21

Abstract: Many management strategies exist for neuroendocrine liver metastases. These strategies range from surgery to ablation with various interventional radiology procedures, and include both regional and systemic therapy with diverse biological, cytotoxic, or targeted agents. A paucity of biological, molecular, and genomic information and an absence of data from rigorous trials limit the validity of many publications detailing management. This Review represents the views from an international conference, for which 15 expert working groups prepared evidence-based assessments addressing specific questions, and from which an independent jury derived final recommendations. The aim of the conference was to review the existing approaches to neuroendocrine liver metastases, assess the evidence on which management decisions were based, develop internationally acceptable recommendations for clinical practice (when evidence was available), and make recommendations for clinical and research endeavours. This report represents the final clinical statements and proposals for future research.

PMID: 24384494 [PubMed - in process]

Read full text

 

Velikyan, Irina

Theranostics 2014; 4(1):47-80. doi: 10.7150/thno.7447

Abstract

Positron Emission Tomography (PET) experienced accelerated development and has become an established method for medical research and clinical routine diagnostics on patient individualized basis. Development and availability of new radiopharmaceuticals specific for particular diseases is one of the driving forces of the expansion of clinical PET. The future development of the 68Ga-radiopharmaceuticals must be put in the context of several aspects such as role of PET in nuclear medicine, unmet medical needs, identification of new biomarkers, targets and corresponding ligands, production and availability of 68Ga, automation of the radiopharmaceutical production, progress of positron emission tomography technologies and image analysis methodologies for improved quantitation accuracy, PET radiopharmaceutical regulations as well as advances in radiopharmaceutical chemistry. The review presents the prospects of the 68Ga-based radiopharmaceutical development on the basis of the current status of these aspects as well as wide range and variety of imaging agents.

Read full text

Lewis MA, Yao JC

Curr Opin Endocrinol Diabetes Obes 2014, 21:000-000, e-published ahead of print

Abstract

Purpose of review: Neuroendocrine tumours (NETs) of the luminal gastrointestinal tract and pancreas are increasing in incidence and prevalence. Prior assumptions about the benign nature of 'carcinoids' and the clinical importance of distinguishing functional vs. nonfunctional tumours are being overturned through greater understanding of disease behaviour and heterogeneity. This review highlights the most contemporary genetic and molecular insights into gastroenteropancreatic NETs.

Recent findings: Biomarkers such as neuron-specific enolase or chromogranin A could be supplemented or supplanted by PCR-based analysis of NET genes detectable in the blood transcriptome. Conventional pathology, including Ki67 testing, could be enhanced with immunohistochemistry and exome analysis. Prognostic markers and/or putative therapeutic targets uncovered through recent studies include heparanase, Id, ATM, SRC, EGFR, hsp90 and PDGFR.
Summary: After a long-standing paucity of options for conventional cytotoxic therapy, the comprehension and treatment of gastroenteropancreatic NETs has been enriched by advancements in taxonomy, molecular pathology and genetic/epigenetic testing.
Video abstract available: See the Video Supplementary Digital Content 1,  http://links.lww.com/COE/A4.

Read full text

 

PLOS One, 2013 May

Modlin IM, Drozdov I, Kidd M 

Abstract: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are increasing in both incidence and prevalence. A delay in correct diagnosis is common for these lesions. This reflects the absence of specific blood biomarkers to detect NENs. Measurement of the neuroendocrine secretory peptide Chromogranin A (CgA) is used, but is a single value, is non-specific and assay data are highly variable. To facilitate tumor detection, we developed a multi-transcript molecular signature for PCR-based blood analysis. NEN transcripts were identified by computational analysis of 3 microarray datasets: NEN tissue (n = 15), NEN peripheral blood (n = 7), and adenocarcinoma (n = 363 tumors). The candidate gene signature was examined in 130 blood samples (NENs: n = 63) and validated in two independent sets (Set 1 [n = 115, NENs: n = 72]; Set 2 [n = 120, NENs: n = 58]). Comparison with CgA (ELISA) was undertaken in 176 samples (NENs: n = 81). 51 significantly elevated transcript markers were identified. Gene-based classifiers detected NENs in independent sets with high sensitivity (85–98%), specificity (93–97%), PPV (95–96%) and NPV (87–98%). The AUC for the NEN gene-based classifiers was 0.95–0.98 compared to 0.64 for CgA (Z-statistic 6.97–11.42, p,0.0001). Overall, the gene-based classifier was significantly (x2 = 12.3, p,0.0005) more accurate than CgA. In a sub-analysis, pancreatic NENs and gastrointestinal NENs could be identified with similar efficacy (79–88% sensitivity, 94% specificity), as could metastases (85%). In patients with low CgA, 91% exhibited elevated transcript markers. A panel of 51 marker genes differentiates NENs from controls with a high PPV and NPV (.90%), identifies pancreatic and gastrointestinal NENs with similar efficacy, and confirms GEP-NENs when CgA levels are low. The panel is significantly more accurate than the CgA assay. This reflects its utility to identify multiple diverse biological components of NENs. Application of this sensitive and specific PCR-based blood test to NENs will allow accurate detection of disease, and potentially define disease progress enabling monitoring of treatment efficacy.

Read full text

J Clin Invest. 2013 May 15

Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR, Zhang L, Thorland EC, Minn KT, Tentu R, Eckloff BW, Wieben ED, Wu Y, Cunningham JM, Nagorney DM, Gilbert JA, Ames MM, Beutler AS.

Abstract: Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0-0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.

PMID: 23676460 [PubMed - as supplied by publisher]

READ full text

The Oncologist, published online April 24, 2013 Yao JC, Reidy Lagunes D, Kulke MH

Abstract
In the past 3 years, we have witnessed the completion of four randomized phase III studies in neuroendocrine tumors and the approval of two new drugs, everolimus and sunitinib, for the treatment of patients with well-differentiated pancreatic neuroendocrine tumors. These studies demonstrate a shift from case series and single-arm studies toward prospective, randomized controlled clinical trials and evidence-based therapy in the neuroendocrine tumor field. However, the clinical development of these agents also highlights the potential challenges awaiting other new drugs in this area. Herein, we discuss the strengths and weaknesses of the most recent phase II and phase III neuroendocrine tumor studies and discuss how limitations inherent in current trial design can lead to potential pitfalls. We also discuss how trial design can be improved, with the hope of increasing the number of drugs successfully developed to treat patients with neuroendocrine tumors. PMID: 23615698 PubMed - [as supplied by publisher]

Read full text

World J Gastroenterolo 2013 April 21; 19(15): 2348-2354 Strosberg J, Casciano R, Stern L, Parikh R, Chulikavit M, Willet J, Liu Z, Wang X, Grzegorzewski KJ

AIM: To assess advanced neuroendocrine tumor (NET) treatment patterns and resource utilization by tumor progression stage and tumor site in the United States.

Read full text.

  • Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options.
    Curr Opin Endocrinol Diabetes Obes. 2013 Mar 11. [Epub ahead of print]
    Vicha A, Musil Z, Pacak K.
     
    PURPOSE OF REVIEW:
    To summarize the recent advances in the genetics of pheochromocytoma and paraganglioma (PHEO/PGL), focusing on the new susceptibility genes and dividing PHEOs/PGLs into two groups based on their transcription profile.
    RECENT FINDINGS:
    Recently, TMEM127, MYC-associated factor X, and hypoxia-inducible factor (HIF) 2α have been described in the pathogenesis of PHEOs/PGLs. Thus, now about 30-40% of these tumors are linked to the germline mutations, which also include mutations in the VHL, RET, NF1, SDHx, and SDHAF2 genes. Furthermore, PHEOs/PGLs have been divided into two groups, cluster 1 (SDHx/VHL) and cluster 2 (RET/NF1), based on the transcription profile revealed by genome-wide expression microarray analysis.
    SUMMARY:
    PHEOs/PGLs are the most inherited tumors among (neuro)endocrine tumors. Future approaches in genetics, including whole-genome sequencing, will allow the discovery of additional PHEO/PGL susceptibility genes. The current division of PHEOs/PGLs into cluster 1 and 2 provides us with additional knowledge related to the pathogenesis of these tumors, including the introduction of new treatment options for patients with metastatic PHEOs/PGLs. New discoveries related to the role of the HIF-1/HIF-2α genes in the pathogenesis of almost all inherited PHEOs/PGLs may call for a new regrouping of these tumors and discoveries of new treatment targets.
    PMID: 23481210 [PubMed - as supplied by publisher]

 

  • Advances in Pulmonary Neuroendocrine Tumor ManagementAdvances in Pulmonary Neuroendocrine Tumor Management
    97 pages
    March, 2013
    Copyright © 2013 Future Medicine Ltd
    doi: 10.2217/9781780841625
    eISBN (PDF): 978-1-78084-162-5
  • Advances in Pulmonary Neuroendocrine Tumor Management by Kjell Oberg
    The spectrum of neuroendocrine tumors (NETs) of the lung include on the one hand typical carcinoids and atypical carcinoids with a more indolent behavior and, on the other hand, the highly aggressive poorly differentiated large- and small-cell carcinomas. Pulmonary NETs account for approximately 25% of all malignant lung cancers, the vast majority being represented by small-cell lung carcinoma. Carcinoid tumors are much rarer and do not exceed 2% of all malignant lung tumors, most of them being typical carcinoids. Despite typical carcinoid tumors having been considered benign, it is has become clear for many years that the fraction of these tumors metastasize not only to local lymph nodes in the mediastinum but also with the liver and bone. Therefore, these tumors, although considered to be benign, need to be followed up for very long periods of time, at least 10 years after operation, but late recurrences up to 15 years after the primary operation have been reported [1–4].

    A classification system has developed by the WHO that combines architectural growth patterns of tumor cells with mitotic index and the presence of necrosis of the purpose of recognising the four different categories purposed in the spectrum of pure lung NETs [1]. In the future, a new classification system will emerge that will hopefully resemble the classification system that has been developed for gastrointestinal NETs. No established treatment for bronchial carcinoid tumors that is based on large randomized control trials has been established so far. However, surgery is recommended as first-line treatment in all cases if possible, including exploration of the mediastinum lymph nodes. Local regional treatment of liver metastases includes radiofrequency ablation, radio- or chemo-embolization, whereas peptide receptor radionuclide therapy (PRRT) can be considered for patients with more widespread disease. The medical treatment has by tradition included biotherapy for the slow-growing tumors such as typical carcinoid tumors with somatostatin analogs and IFN-α as a basis. More recently, everolimus and sunitinib have been applied in smaller series. Atypical carcinoids with higher proliferation can be subjected to chemotherapy, including streptozotocin plus fluorouracil, the old treatment, but more recently temozolomide ± capecitabine. In the more extreme cases with mitotic index >10, cisplatinum plus etoposide can still be considered as standard of care but can also be replaced by temozolomide + capecitabine + bevacizumab [5,6]. In in vitro studies, a combination of EGF receptor inhibitors (erlotinib) in combination with everolimus exerts synergistic effect in inducing apoptosis in atypical carcinoid cell lines [7]. A problem might be that this is too toxic to be applied in patients. The c-Met oncogene is an alternative target for specific antiproliferative therapies and has been investigated in other tumor models and has also been looked at in small-cell lung carcinoma [8]. Very important steps forward for the new classification tumor biology-based system development of new markers for early recurrence as well as response to treatment are warranted. Such biomarkers are still lacking. However, molecular imaging seems very promising with new tracers that can be applied for localization, early detection of recurrence and also possible indicator of response. Such tracers are 68Ga-DOTATATE/DOTATOC but FDG PET/CT also gives valuable information about the aggressiveness and proliferation of the tumor. We will hopefully see development of new biomarkers in the future. This book also includes a specific chapter on small-cell lung cancer as well as large-cell neuroendocrine carcinoma (Chapter 5), which are completely different types of NETs compared with the more indolent typical and atypical bronchial carcinoids.

    Finally, a specific chapter on thymic carcinoids (Chapter 6) is included because this rather rare NET is gaining more and more attention and can present with florid clinical pictures, such as Cushing syndrome, particularly in patients with multiple endocrine neoplasia type 1. This tumor type is mostly aggressive with a tendency to metastasize early and worse prognosis. The treatment is not essentially different from the different subtypes of bronchial or lung NETs.

  • Practical Guide to Supportive Care of Patients With Functional Neuroendocrine Tumors

    Semin Oncol 2013 40:45-55
    Anthony, Lowell B.

    Abstract: Supportive care of patients with functional neuroendocrine tumors (NETs) has evolved to include the use of multiple targeted agents to control paraneoplastic states and newer surgical and interventional radiologic techniques to reduce tumor bulk. Challenges encountered by the clinician are the recognition of specific symptom complexes, selecting the relevant laboratory tests and radiologic/scintigraphic scans, and the timing of intervention(s). Individual variables such as the severity of symptoms in the context of primary and metastatic disease sites, tumor bulk, comorbidities, and previous treatment are factors determining the prioritization of specific treatment regimens for patients with functional NETs. Symptoms such as flushing, secretory diarrhea, hypercalcemia, hyper/hypoglycemia, hypercortisolism, and peptic ulcers should improve with decreasing the elevated amino acid and/or peptide levels produced by NETs. These paraneoplastic symptoms may be accompanied by complaints related to tumor burden such as fatigue, pain, early satiety, anorexia, weight loss, night sweats, and/or symptoms secondary to adverse drug effectssuch as mucositis, dysgeusia, diarrhea, rash, hypertension, and myelosuppression. Developing a comprehensive continuum of care plan early in disease management assists in controlling the presenting signs and symptoms, and in minimizing disease- and/or treatment-related side effects. This guide serves as a framework to manage the signs and symptoms of metastatic functional neuroendocrine tumors.

READ full text here.

The Oncolgist 2013;18:46-53

Castellano D, Bajetta E, Panneerselvam A, Saletan S, Kocha W, O'Dorisio T, Anthony LB, Hobday T

Abstract: Introduction. The incidence of colorectal neuroendocrine tumors (NETs) is increasing, and patients with this disease have particularly poor prognoses. Treatment options are limited, and survival times have not improved in the past decade. Methods. A post hoc analysis of the efficacy and tolerability of everolimus plus octreotide long-acting repeatable (LAR) was conducted in patients with colorectal NETs enrolled in the phase III RAD001 in Advanced Neuroendocrine Tumors, Second Trial (RADIANT-2) study. The primary endpoint (progression-free survival [PFS]), secondary endpoints (including objective response rate), and safety were assessed. Results. Patients with colorectal NETs receiving everolimus plus octreotide LAR had a significantly longer median PFS (29.9 months; n = 19) than did those receiving placebo plus octreotide LAR (6.6 months; n = 20). Everolimus plus octreotide LAR treatment also significantly reduced the risk for disease progression (hazard ratio: 0.34; 95% confidence interval: 0.13-0.89; p = .011). Although no objective responses were observed, tumor shrinkage was more frequently noted in the everolimus plus octreotide LAR arm than in the placebo plus octreotide LAR arm (67% vs. 37%, respectively). The combination of everolimus plus octreotide LAR was generally well tolerated by patients with colorectal NETs; rash and stomatitis were the most commonly reported adverse events. Conclusions. Everolimus plus octreotide LAR treatment had significant benefits and improved outcomes for patients with advanced colorectal NETs compared with placebo plus octreotide LAR treatment. Results of this exploratory analysis are consistent with those reported from the RADIANT-2 primary analysis. These findings support additional investigations of everolimus plus octreotide LAR in patients with colorectal NETs.

PMID: 23263288[PubMed - in process]

READ full text

JCO. Feb 1, 2013; vol. 31, no. 4, 404-405 [Epub ahead of print] Kulke, M

Read full text

J Clin Endocrinol Metab. 2012 Jun 20. [Epub ahead of print]                    Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML                                                                                           

Abstract: Objective:The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple endocrine neoplasia type 1 (MEN1).Participants:The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration.Process:Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated.Conclusions:MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develop carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, and lipomas. Patients with MEN1 have a decreased life expectancy, and the outcomes of current treatments, which are generally similar to those for the respective tumors occurring in non-MEN1 patients, are not as successful because of multiple tumors, which may be larger, more aggressive, and resistant to treatment, and the concurrence of metastases. The prognosis for MEN1 patients might be improved by presymptomatic tumor detection and undertaking treatment specific for MEN1 tumors. Thus, it is recommended that MEN1 patients and their families should be cared for by multidisciplinary teams comprising relevant specialists with experience in the diagnosis and treatment of patients with endocrine tumors.
PMID: 22723327 [PubMed - as supplied by publisher]

 

  • Management of neuroendocrine tumors in children, adolescents, and young adults
    J Pediatr Hematol Oncol May 2012;34 Suppl 2:S64-68
    Howell D, O'Dorisio MS

    Abstract: Neuroendocrine tumors, often referred to as carcinoid
    tumors, are relatively rare within the pediatric and young adult
    populations. However, when they do occur, the more aggressive
    tumors can be associated with significant morbidity and even
    mortality in this younger age group. This article reviews the history
    of pediatric neuroendocrine tumors, typical clinical presentation,
    appropriate diagnostic studies, staging, and treatment of this unusual
    cancer.

    PMID: 22525409 [PubMed - in process]

    READ full text

  • The management of neuroendocrine tumours: current and future medical therapy options.                                                                                  Clin Oncol (R Coll Radiol). 2012 May;24(4):282-93. Epub 2011 Sep 9. Oberg, KE.
    Source: Department of Endocrine Oncology, University Hospital, SE-751 85 Uppsala, Sweden.

    Abstract: Neuroendocrine tumours (NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); both types frequently synthesise more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources, the incidence and prevalence of NETs is increasing. The primary treatment goal for patients with NETs is curative, with symptom control and the limitation of tumour progression as secondary goals. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require chronic postoperative medical management with the aim of relieving symptoms and, in recent years, suppressing tumour growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilise tumour growth in many patients. Results from the PROMID study show that octreotide LAR 30mg is an effective antiproliferative treatment in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut NETs. An antiproliferative effect can also be achieved with everolimus, and combination therapy with octreotide LAR has shown synergistic antiproliferative activity. In the future, pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumour cell proliferation. Peptide receptor radiotherapy with [90]yttrium-DOTATOC or [177]lutetium-DOTATE is also a new interesting treatment option for NETs.

    Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

    PMID: 21907552 [PubMed - in process]

  • The risk of metachronous cancers in patients with small intestinal carcinoid tumors: a US population-based study.

    Endocr Relat Cancer. 2012 March 27 [Epub ahead of print]

    Amin S, Warner RR, Itzkowitz SH, Kim MK.

    Source: S Amin, Internal Medicine, Mount Sinai School of Medicine, New York, United States.

    Abstract: Small intestinal carcinoids (SIC) are the most common small bowel malignancies. We sought to determine the risk of developing SIC before and after other primary malignancies (PM) and the prognosis of patients with SIC, with and without another PM. We used the SEER database was used to identify patients diagnosed with SICs between 1973-2007. Multiple primary-standardized incidence ratios were calculated as an approximation of relative risk (RR) to explore the association of SICs with metachronous malignancies. Survival analysis was performed using Kaplan-Meier methods and Cox proportional-hazard models. Among 8,331 patients with SICs, 2,424 (29%) had another PM at some time. The most common sites were prostate (26.2%), breast (14.3%), colon (9.1%), lung/bronchus (6.3%), and bladder (5.3%). 67% had a PM diagnosed before the SIC (pre-SIC), 33% after (post-SIC), and 8% had a PM both before and after SIC. Among the pre-SIC group, the risk of future SIC was increased after cancers of the small bowel (RR11.86[95%CI6.13-20.72]), esophagus (4.05[1.10-10.36]), colon (1.39[1.05-1.81]), kidney (1.93[1.12-3.09]), prostate (1.38[1.17-1.62]), and leukemia (2.15[1.18-3.61]). Among the post-SIC group, there was an increased risk of future PM of the small bowel (8.78[4.54-15.34]), liver (2.49[1.08-4.91]), prostate (1.25[1.0-1.53]), and thyroid (2.73[1.10-5.62]). Compared to patients with only SIC, those with a PM pre-SIC had worse mean survival (57.9vs.40.9 months, HR1.55[1.42-1.69],p<0.001). In conclusion, almost one-third of patients with SICs have an associated metachronous primary tumor. When these primaries occur prior to (but not after) the SIC diagnosis, the prognosis is worse than with an initial SIC. The type of malignancies associated with SICs may guide future screening efforts.

    PMID: 22454400 [PubMed - as supplied by publisher]

  • Current Scientific Rationale for the Use of Somatostatin Analogs and mTOR Inhibitors in Neuroendocrine Tumor Therapy.

    J Clin Endocrinol Metab. 2011 Dec 14. [Epub ahead of print]

    Bousquet C, Lasfargues C, Chalabi M, Moatassim Billah S, Susini C, Vezzosi D, Caron P, Pyronnet S.

    Abstract Context:Among the innovative molecules used to manage neuroendocrine tumors, there is growing interest in combining the somatostatin analogs octreotide or pasireotide (SOM230) and everolimus (RAD001), an inhibitor that targets the protein kinase mammalian target of rapamycin (mTOR).Evidence Acquisition:The aims of this review were to describe the signaling pathways targeted independently by somatostatin analogs and everolimus and to summarize the scientific rationale for the potential additive or synergistic antitumor effects of combined therapy.Evidence Synthesis:The somatostatin analogs (octreotide and lanreotide) have potent inhibitory effects on hypersecretion, thereby alleviating the symptoms associated with neuroendocrine tumors. Furthermore, the antitumor potential of octreotide is now well documented. Pasireotide, a somatostatin analog, has the advantage of targeting a wider range of somatostatin receptors (subtypes 1, 2, 3, and 5) than the analogs previously used in clinical practice (which preferentially target subtype 2) and thus has a broader spectrum of activity. Everolimus is a rapamycin analog that inhibits mTOR, but it is more soluble than rapamycin and can be administered orally. mTOR is a protein kinase involved in many signaling pathways, primarily those initiated by tyrosine kinase receptors. Sustained mTOR activity leads to the induction of cell growth, proliferation, and cell survival. Everolimus therefore has obvious potential in cancer therapy.Conclusions:The combination of somatostatin analogs and everolimus in therapeutic trials offers a promising treatment option for neuroendocrine tumors.

    PMID:22170729 [PubMed - as supplied by publisher]

  • Management of Neuroendocrine Tumors of Unknown Origin

Polish A, Vergo MT, Agulnik M

J Natl Compr Canc Netw. 2011;9(12):1397-1403

Abstract: Neuroendocrine tumors (NETs) of unknown origin account for more than 10% of all NETs. Most of these tumors are poorly differentiated and, thus, very aggressive. Establishing the location of the primary tumor can be challenging. Workup of these NETs of unknown origin includes a thorough family history, immunohistochemistry, imaging, and OctreoScan. If the location of the primary malignancy is not determined, treatment is often initiated based on the grade and level of differentiation of the tumor, with well- and moderately differentiated tumors treated as carcinoid tumors, whereas poorly differentiated tumors are treated similarly to small cell tumors. Therapy is chosen based on symptoms and with the goal of debulking tumor when feasible and safe.

READ full text article.

  • Treatment of liver metastases in patients with neuroendocrine tumors: a comprehensive review.
    Int J Hepatol. 2011;2011:154541. doi: 10.4061/2011/154541. Epub 2011 Oct 13.

    Harring TR, Nguyen NT, Goss JA, O'Mahony CA.

    Patients diagnosed with Neuroendocrine Tumors (NET) often are also diagnosed with Neuroendocrine Liver Metastases (NLM) during the course of their disease. NLM can cause significant morbidity and mortality, oftentimes much more than compared to patients with NET. Treatment options have been limited in the past, focusing on surgical resections, for which only a minority of patients are candidates. However, developments of new treatment modalities have progressed rapidly and patients with NLM now have significantly more options, including surgical-directed therapies; liver-directed therapies; and nonsurgical, non-liver-directed therapies. This review provides information about the roles of hepatic resection, orthotopic liver resection, radiofrequency ablation, hepatic artery embolization and hepatic artery chemoembolization, hepatic artery radioembolization and selective internal radiation therapy, peptide receptor radionuclide therapy, systemic chemotherapy, biotherapies including somatostatin analogs and interferon-α, vascular endothelial growth factor and mTOR targets, and microRNA-regulated pathways. Given these new options, the clinician can tailor therapy specific to the patient diagnosed with NLM, thereby giving the patient the best possible chance of prolonged survival.

    Read full-text article

    PMID: 22013537 [PubMed]
    PMCID: PMC3195553

Strosberg JR, Cheema A, Kvols, LK

Cancer Control. 2011 April;18(2):127-37

Background:  Treatment options for metastatic gastroenteropancreatic neuroendocrine tumors (NETs) have evolved in recent years. The somatostatin analogs octreotide and lanreotide have long been used for management of symptoms such as flushing and diarrhea associated with hormonally active NETs. New evidence demonstrates that these agents can also inhibit tumor growth. Other novel agents targeting the VEGF and mTOR pathways have recently been investigated in multicenter phase III studies. 

READ full-text article.

PMID: 21451455 [PubMed - in process]

Ardill JES, O'Dorisio TM

Endocrinol Metab Clin N Am 39 (2010) 777-790

Abstract: Neuroendocrine tumors (NETs) are difficult to diagnose. Their symptoms may be vague or intermittent, and are frequently associated with much more common diseases; many of the tumors may be asymptomatic. Therefore, diagnosis can be delayed for some years. Because most NETs are secretory, the measurement of circulating biomarkers is helpful not only for diagnosis but also for assessing tumor response to treatment, monitoring disease progression, and use as prognostic indicators.

READ full text, PDF.

Kaltsas G, Andoulakis II, de Herder WW, Grossman, AB

Endocrine-Related Cancer. 2010 Jul 28;17(3):R173-R193 Print  2010 Sept

Abstract: Neuroendocrine tumours may be either benign or malignant tumours, and have the ability to synthesise and secrete biologically active substances characteristic of the cell of origin that can cause distinct clinical syndromes. The term ‘paraneoplastic syndromes’ (PNSs) is used to denote syndromes secondary to substances secreted from tumours not related to their specific organ or tissue of origin and/or production of autoantibodies against tumour cells; such syndromes are mainly associated with hormonal and neurological symptoms. Appreciation of the presence of such syndromes is important as clinical presentation, if not identified, may delay the diagnosis of the underlying neoplasia. Conversely, early recognition can allow for more rapid diagnosis, particularly as the coexistence of a neoplasm with a clinical or biochemical marker offers an additional determinant of tumour status/progression. PNSs can complicate the patient’s clinical course, response to treatment, impact prognosis and even be confused as metastatic spread.
Their diagnosis involves a multidisciplinary approach, and detailed endocrinological, neurological, radiological and histological studies are required. Correct diagnosis is essential as the treatment of choice will be different for each disorder, particularly in the case of malignant tumours; it is therefore important to develop appropriate means to correctly identify and localise these tumours. Clinical awareness and the incorporation into clinical practise of 111In-octreotide scintigraphy, chromogranin A and other evolving biochemical marker measurement techniques have substantially contributed to the identification of patients harbouring such syndromes. Disease specific medical therapies are mandatory in order to prevent recurrence and/or further tumour growth. Owing to their rarity, central registration of these syndromes is very helpful in order to be able to provide evidence-based diagnostic and therapeutic approaches.

Read full-text article

PMID: 20530594 [PubMed - indexed for MEDLINE]

 

Gilbert JA, Adhikari LJ, Lloyd RV, Rubin J, Haluska P, Carboni JM, Gottardis MM, Ames MM.

Endocr Relat Cancer. 2010 Jun 25;17(3):623-36. Print 2010

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA

Abstract: Neuroendocrine (carcinoid) tumors (NETs) are endocrine neoplasms occurring most frequently in gastrointestinal and bronchopulmonary (BP) systems. The majority of patients present with advanced disease for which few treatment options exist. We assessed 104 NETs (74 cases) for biomarkers targeted by anticancer drugs under development for other forms of cancer. Activating mutations were assessed in epidermal growth factor receptor (EGFR), stem cell factor receptor (KIT), and platelet-derived growth factor receptor alpha (PDGFRA), as well as non-response mutations in KRAS. Copy number of EGFR and HER-2/neu was quantified with fluorescence in situ hybridization. Immunohistochemical analyses were performed for EGFR, KIT, PDGFRA, somatostatin receptor subtypes 2A and 5 (SSTR5), vascular endothelial growth factor receptor 1, mammalian target of rapamycin (mTOR), insulin-like growth factor 1 receptor (IGF1R), heat shock protein 90 (Hsp90), and transforming growth factor-beta receptor 1 (TGFBR1). NETs lacked HER2-overexpression predictive of anti-HER2 response and KIT and PDGFRA activating mutations indicative of imatinib sensitivity. High EGFR aneusomy (20% of all cases) and elevated EGFR copy number (39%) were found, but few KRAS mutations associated with non-response to anti-EGFR therapy (3%). Hsp90, TGFBR1, IGF1R, and SSTR5 exhibited highest levels of immunohistochemical staining in the largest percents of tumors. In subsequent in vitro studies, anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) (targeting Hsp90) inhibited proliferation of BP NET lines NCI-H727, NCI-H720, and NCI-H835 with IC(50) values of 70.4, 310, and 788 nM respectively; BMS-754807 (targeting IGF1R/IR) inhibited growth with IC(50) values of 428 nM, 2.8 microM, and 1 microM. At growth-inhibiting concentrations, 17-AAG (24 h) induced loss of EGFR and IGF1R in the IGF1R-expressing NCI-H727 line, and BMS-754807 (24 h) inhibited constitutive IGF1R autophosphorylation. Our results support further research into Hsp90, IGF1R, and EGFR as targets for developing new anticancer therapeutics for some NETs.

PMID: 20385747 [PubMed - indexed for MEDLINE]

 

Nissen NN, Kim AS, Yu R, Wolin EM, Friedman ML, Lo SK, Wachsman AM, Colquhoun SD.

Am Surg. 2009 Oct;75(10):1025-9.

Department of Surgery, Center for Liver Diseases and Transplantation, Cedars-Sinai Medical Center, 8635 W 3rd Street, Suite 590W, Los Angeles, CA 90048, USA. nissenn@cshs.org

Abstract: Pancreatic neuroendocrine tumors (pNETs) are an uncommon pancreatic neoplasm. We reviewed the presentation, management, and outcome of patients with pNETs treated at a single center by a multidisciplinary approach between 2004 and 2008. Over this time period, 154 patients with carcinoid and neuroendocrine tumors were treated, which included 46 patients (30% of total) with pNETs. The most common presentations included abdominal pain (20 of 46 [43%]), systemic symptoms such as hypoglycemia (15 of 46 [33%]), and incidental mass (7 of 46 [15%]). Fourteen patients had functional tumors. At the time of diagnosis, 22 patients (48%) presented without metastases and 24 (52%) had metastatic disease. Median follow up for the entire group was 42 months. All patients with nonmetastatic pNET underwent pancreatic resection with 95 per cent postoperative survival. Overall survival in this group at 3 years was 86 per cent and disease-free survival was 81 per cent. In patients presenting with metastatic pNET, multiple treatment modalities were used, including liver resection or ablation (n = 15), hepatic chemoembolization (n = 17), pancreatic resection (n = 12), and systemic treatments (n = 7). Three-year survival was 70 per cent. Pancreatic resection results in greater than 80 per cent 3-year survival in nonmetastatic pNET. In patients presenting with metastatic pNET, excellent survival rates are also achievable using a multidisciplinary multimodal approach.

PMID: 19886158 [PubMed - indexed for MEDLINE]

Strosberg J, Nasir A, Coppola D, Wick M, Kvols L.

Hum Pathol. 2009 Sep;40(9):1262-8. Epub 2009 Apr 14

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. jonathan.strosberg@moffitt.org

Abstract: Three-tiered grading systems (low, intermediate, and high grade) have been proposed for neuroendocrine tumors. These classifications have not been rigorously evaluated in neuroendocrine malignancies of the digestive tract. We performed a retrospective chart analysis of 83 patients with metastatic gastroenteropancreatic neuroendocrine tumors, correlating tumor grade with overall survival. We also analyzed available biopsy specimens (on 40 patients), examining hematoxylin and eosin stains for mitotic rate and immunostaining for measurement of the Ki-67 index. Tumor grades were assigned based on the mitotic rate and the Ki-67 index, and the prognostic validity of each grading method was assessed. A highly significant correlation existed between the reported tumor grade and overall survival. Five-year survival rates for patients with low-, intermediate-, and high-grade tumors were 87%, 38%, and 0%, respectively. On biopsy specimen analysis, both mitotic rates and Ki-67 indexes correlated strongly with overall survival. We conclude that a 3-tiered grading classification for gastroenteropancreatic neuroendocrine tumors correlates with survival in the metastatic setting. Both mitotic rates and Ki-67 indexes are inversely associated with survival and can be analyzed independently for assignment of grade.

PMID: 19368957 [PubMed - indexed for MEDLINE]

      Ola Nilsson1, Yvonne Arvidsson1, Viktor Johanson2, Eva Forssell-Aronsson3 and Håkan Ahlman2,*
      Departments of Pathology1, Surgery2 and Radiation Physics3 at the   Sahlgrenska Academy, University of Gothenburg, Gothenburg,
Sweden

      Anti-Cancer Agents in Medicinal Chemistry, 2010; 10:250-269

      CLICK HERE for full text.

          Abstract:Patients with well-differentiated neuroendocrine tumours of the gastrointestinal tract often present with metastases and hormonal symptoms. These patients can be palliated by interventional tumour reduction and medical treatment with somatostatin analogues; no effective chemotherapy is available. Radionuclide therapy via somatostatin receptors is one new therapeutic alternative. The recognition that neuroendocrine tumours express specific receptors for growth factors and chemokines, which are of importance for tumour growth, vascularization, and spread, may open the way for new therapeutic approaches. The signalling pathways in carcinoid tumours are incompletely explored. This review summarizes potential new treatment strategies from clinical and experimental studies, e.g. inhibition of angiogenesis, targeting of growth factors or their receptors by tyrosine kinase inhibitors, interference with specific cellular pathways (mTOR, PI3K, RAS/RAF, Notch), and also inhibition of the proteasome and histone deacetylation. Combining targeted therapy with chemotherapy, or using drugs to sensitize for radionuclide therapy, may enhance the treatment outcome.

PMID: 20406194

*Address correspondence to this author at the Department of Surgery, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden;Tel:+46-31-3421778; E-mail: hakan.ahlman@surgery.gu.se

Tina Binderup, Ulrich Knigge, Annika Loft, Jann Mortensen, Andreas Pfeifer, Birgitte Federspiel, Carsten Palnaes Hansen, Liselotte Højgaard, and Andreas Kjaer

Authors’ Affiliations: Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark; Cluster for Molecular Imaging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

J Nucl Med 2010; 51:704–712

Abstract: Functional techniques are playing a pivotal role in the imaging of cancer today. Our aim was to compare, on a head-to-head basis, 3 functional imaging techniques in patients with histologically verified neuroendocrine tumors: somatostatin receptor scintigraphy (SRS) with 111Indiethylenetriaminepentaacetic acidoctreotide, scintigraphy with 123I-metaiodobenzylguanidine (MIBG), and 18F-FDG PET. Methods: Ninety-six prospectively enrolled patients with neuroendocrine tumors underwent SRS, 123I-MIBG scintigraphy, and 18F-FDG PET on average within 40 d. The functional images were fused with low-dose CT scans for anatomic localization, and the imaging results were compared with the proliferation index as determined by Ki67. Results: The overall sensitivity of SRS, 123I-MIBG scintigraphy, and 18F-FDG PET was 89%, 52%, and 58%, respectively. Of the 11 SRS-negative patients, 7 were 18F-FDG PET-positive, of which 3 were also 123I-MIBG scintigraphy–positive, giving a combined overall sensitivity of 96%. SRS also exceeded 123I-MIBG scintigraphy and 18F-FDG PET based on the number of lesions detected (393, 185, and 225, respectively) and tumor subtypes. 123I-MIBG scintigraphy was superior to 18F-FDG PET for ileal neuroendocrine tumors, and 18F-FDG PET was superior to 123I-MIBG scintigraphy for pancreaticoduodenal neuroendocrine tumors. The sensitivity of 18F-FDG PET (92%) exceeded that of both SRS (69%) and 123I-MIBG scintigraphy (46%) for tumors with a proliferation index above 15%. Conclusion:The overall sensitivity of 123I-MIBG scintigraphy and 18F-FDG PET was low compared with SRS. However, for tumors with a high proliferation rate, 18F-FDG PET had the highest sensitivity. The results indicate that, although SRS should still be the routine method, 18F-FDG PET provides complementary diagnostic information and is of value for neuroendocrine tumor patients with negative SRS findings or a high proliferation index.

PMID: 20395333 [PubMed - as supplied by publisher]

Mackenzie R. Cook, Scott N. Pinchot, Renata Jaskula-Sztul, Jie Luo, Muthusamy Kunnimalaiyaan, and Herbert Chen

Authors’ Affiliations: Endocrine Surgery Research Laboratory, University of Wisconsin, and the University of Wisconsin Carbone Cancer Center, Madison, Wisconsin

Mol Cancer Ther. 9(2); 429–37. 2010 Jan 26

Abstract: Carcinoids are neuroendocrine tumors (NET) that secrete hormones, including serotonin, resulting in the malignant carcinoid syndrome. In addition to the significant morbidity associated with the syndrome, carcinoids are frequently metastatic at diagnosis, and untreated mortality at 5 years exceeds 70%. Surgery is the only curative option, and the need for other therapies is clear. We have previously shown that activation of Raf-1 inhibits carcinoid cell proliferation. We investigated the ability of leflunomide (LFN), a Food and Drug Administration–approved medication for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide (TFN) as a potential anti-NET treatment. LFN and TFN inhibit the in vitro proliferation of gastrointestinal carcinoid cells and induce G2-M phase arrest. Daily oral gavage of nude mice with subcutaneous xenografted carcinoid tumors confirms that LFN can inhibit NET growth in vivo. Treatment with TFN suppresses the cellular levels of serotonin and chromogranin A, a glycopeptide co-secreted with bioactive hormones.

Additionally, TFN reduces the level of achaete-scute complex-like 1 (ASCL1), a NET marker correlated with survival. These effects are associated with the activation of the Raf-1/mitiogen-activated protein kinase kinase/extracellular signal–regulated kinase-1/2 pathway, and blockade of mitiogen-activated protein kinase kinase signaling reversed the effects of TFN on markers of the cell cycle and ASCL1 expression.

In summary, LFN and TFN inhibit carcinoid cell proliferation in vitro and in vivo and alter the expression of NET markers. This compound thus represents an attractive target for further clinical investigation.

PMID: 20103603 [PubMed-as supplied by publisher]

Maralyn R. Drucea Val Lewingtonb Ashley B. Grossman

Neuroendocrinology. 2010;91(1):1-15. Epub 2009 Jul 7.

Abstract: Neuroendocrine tumours comprise a group of neoplasms with variable clinical behaviour. Their growth and spread is often very slow and initially asymptomatic, and thus they are often metastatic at the time of diagnosis and incurable by surgery. An exciting therapeutic strategy for cytoreduction, both for stabilisation of tumour growth and inhibition of hormone production, is the use of targeted radionuclide therapy. Evidence from large-scale, randomised, placebo controlled trials is very difficult to obtain in these rare diseases, but current data appear promising. It is timely to review the principles underlying the use of these therapies, together with the clinical outcomes to date and potential directions for future research.

PMID: 19590162

Gabriele Capursoaa,1, Nicola Faziobb,1, Stefano Festaaa, Francesco Panzutoaa, Filippo De Braudbb, Gianfranco Delle Faveaaa,*

a Digestive and Liver Disease Unit, S. Andrea Hospital, II Medical School, University “La Sapienza”, Via Di Grottarossa 1035-1039, 00189, Rome, Italy

 b Unit of Clinical Pharmacology and New Drugs, European Institute of Oncology, Milan, Italy

 Critical Reviews in Oncology/Hematology 72 (2009) 110-124

Abstract: Gastroenteropancreatic endocrine tumours (GEP ETs) represent a relatively rare and heterogeneous group of neoplasms whose therapy can be challenging. The poorly differentiated, fast-growing cases are treated with chemotherapy. In the slow-growing ones, biotherapy is usually performed. Several categories of targeted therapies have been studied for their treatment in vitro and in vivo. A critical review of molecular alterations suggests a rationale for targeting angiogenesis, and the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Accordingly, antiangiogenic agents and mTOR inhibitors are presently the most tested agents in phase II and III studies. Bevacizumab, some multitarget inhibitors, and mTOR inhibitors showed promising results in patients with advanced GEP ETs. A limited activity has been reported for imatinib and epidermal growth factor receptor (EGFR) inhibitors. Combinations of molecular targeted therapies with different sites of action, and somatostatin analogues may be relevant to avoid molecular escape pathways. Future trials should include more homogeneous groups of patients and pay more attention to the subgroup with progressive disease.

PMID: 19249226

  • The following information was presented at the ASCO Gastrointestinal Cancers Symposium held in Orlando, Florida from January 22-24, 2010

Updated results of the phase III trial of sunitinib (SU) versus placebo (PBO) for treatment of advanced pancreatic neuroendocrine tumors (NET).

2010 Gastrointestinal Cancers Symposium Abstract 127

E. Raymond, P. Niccoli-Sire, Y. Bang, I. Borbath, C. Lombard-Bohas, J. W. Valle, S. Patyna, D. Lu, R. C. Chao, J. Raoul

Authors' Affiliations: Beaujon University Hospital, Clichy, France; Service d'Oncologie Medicale, CHU La Timone, Marseille, France; Seoul National University Hospital, Seoul, South Korea; Cliniques Universitaires Saint-Luc, Brussels, Belgium; Hopital Edouard Herriot, Lyon, France; The Christie NHS Foundation Trust, Manchester, United Kingdom; Pfizer Oncology, San Diego, CA; Pfizer Oncology, La Jolla, CA; Centre Eugene Marquis, Rennes, France

Background: The multitargeted tyrosine kinase receptor inhibitor sunitinib has shown activity against pancreatic NET in the RIP1-Tag2 mouse model and in phase I/II studies.

Methods: This phase III, multinational, randomized, double-blind trial (NCT00428597) investigated the efficacy and safety of SU vs PBO in patients (pts) with advanced pancreatic NET. Pts with well-differentiated pancreatic islet cell tumors and documented disease progression within the past 12 months were randomized (1:1) to SU 37.5 mg/day daily or PBO. All pts received best supportive care and somatostatin analogs, if indicated. The primary endpoint was progression-free survival (PFS) with target enrolment of 340 pts.

Results: This study was stopped early due to differences in efficacy, as recommended by the independent Data Monitoring Committee. Between Jun 2007 and Apr 2009, 171 pts were randomized to SU (n = 86) or PBO (n = 85); median age was 56 years, 52% were female, 50% had nonfunctional tumors, 95% had metastatic disease, and 71% had received various prior treatments. The most frequently reported adverse events (AEs) with SU were (SU vs PBO, all grades) fatigue/asthenia (60% vs 52%), diarrhea (59% vs 39%), nausea (45% vs 29%) and vomiting (34% vs 31%). Grade 3/4 AEs (SU vs PBO) included neutropenia (12% vs 0%), hypertension (9.6% vs 1.2%), fatigue/asthenia (8.4% vs 12.2%), palmar-plantar erythrodysesthesia (6.0% vs 0%) and abdominal pain (4.8% vs 9.8%). More serious AEs were reported in the PBO arm (26.5% in SU vs 41.5% in PBO). Final analysis of 81 events for PFS included 75 events of disease progression. Median PFS was 11.4 months in the SU arm vs 5.5 months in the PBO arm (p = 0.0001). The objective response rate (ORR) with SU was 9.3% (2 complete and 6 partial responses; 95% CI: 3.2-15.4%). There were 9 and 21 deaths in the SU and PBO arms, respectively.

Conclusions: Sunitinib prolonged PFS, increased ORR and OS, and displayed an acceptable safety profile in pts with advanced pancreatic NET.



 

SU (n = 86)

PBO (n = 85)

Hazard ratio (95% CI)

p


Median PFS, months

11.4

5.5

0.418 (0.263, 0.662)

0.0001

ORR, n (%)

8 (9.3%)

0

-

0.0066

Median OS

NR

NR

0.404 (0.185, 0.882)

0.0186


 

Abbreviations: SU, sunitinib; PBO, placebo; CI, confidence interval; PFS, progression-free survival; ORR, objective response rate; OS, overall survival; NR, not reached.

(Please note: sunitinib is not yet FDA-approved for neuroendocrine tumors)

Raymond E, Faivre S, Hammel P, Ruszniewski P.

Department of Medical Oncology and Gastroenterology,
Beaujon University Hospital, Clichy, France,
eric.raymond@bjn.aphp.fr

Targeted Oncology (2009) 4:253-254

Abstract: Sunitinib demonstrating efficacy in pancreatic islet cell carcinomas will pave the way for further trials in other neuroendocrine tumor types such as carcinoid, poorly differentiated neuroendocrine disease, and several other endocrine tumors that are dependent on VEGF/VEGFR for angiogenesis. In addition, other drugs with distinct mechanisms of action, such as mTOR inhibitors, currently investigated in phase III trials, may also supply novel options in those diseases to control tumor growth and metastasis.

PMID: 19911111 [PubMed – as supplied by publisher]

Ursula Plöckingera Björn Gustafssonb Diana Ivanc Waldemar Szpakd
Joseph Davaree and all other Mallorca Consensus Conference participants

a Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany;
b Medisinsk avd Gastroseksjon, St Olavs Hospital HF, Trondheim, Norway;  
c Endocrinology and Diabetology, Klinikum der Philipps-Universität, Marburg, Germany;
d Westville Hospital, Amanzimototi, Mayville, South Africa;   
e Department of Cardiology, Royal Free Hospital, London, UK

Neuroendocrinology 2009; 90:190-193

Introduction: Carcinoid heart disease is observed in 3–4% of all patients with a neuroendocrine tumor and in 40–50% of those with a carcinoid syndrome [1, 2]. Details on well differentiated neuroendocrine jejunal-ileal tumors have already been discussed in the ENETS Consensus Guidelines and the reader is referred to these Guidelines [3]. Here technical questions and quality management for the diagnosis and follow-up of carcinoid heart disease will be discussed. Involvement of the tricuspid leaflets grade 2–3 occurs in 90%, a stenosis of the pulmonary leaflets in 50%, while regurgitation is seen in 81% of the patients during the course of the disease [4, 5] . Carcinoid heart disease is a relatively late manifestation of neuroendocrine tumors; however, it has an important impact on the prognosis of these patients. Thus, early diagnosis and treatment is mandatory in each patient with a carcinoid syndrome. Echocardiography is the gold standard for detection of carcinoid heart disease. This article will concentrate on technical details for echocardiography. The information provided should help those not experienced with this disease to diagnose carcinoid heart disease and provide high-quality information of echocardiographic investigations. The information provided by echocardiography will be the basis for clinical decisions and may well influence the prognosis and outcome of the patient.

PMID: 19713710 [PubMed – as supplied by publisher]

Catharina M. Korse, Babs G. Taal, Cornelis A. de Groot, Robert H. Bakker, and Johannes M.G. Bonfrer

Journal Clinical Oncology 27:4293-4299

Conclusion: N-terminal pro-brain natriuretic peptide (NT-proBNP) and chromogranin-A (CgA) are very important markers in the diagnosis of CHD in patients with NET. Furthermore, patients with elevated NT-proBNP in addition to elevated CgA levels showed worse overall survival than patients with elevated CgA alone.

PMID: 19667278 [Pubmed – as supplied by publisher]

Bushnell D.
University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA. david-bushnell@uiowa.edu

Journal of the National Comprehensive Cancer Network. 2009 Jul;7(7):760-4.

Abstract: Treatment options in advanced-stage neuroendocrine tumors are limited. A promising new category of therapy was recently introduced for these tumors in which radioactive atoms are attached to molecules that target and bind to neuroendocrine cancer cells. 90Yttrium-DOTA-Phe1-Tyr3-octreotide and radioactive drugs which targets cells by binding to somatostatin receptors. 131Iodine-metaiodobenzylguanidine also targets neuroendocrine tumors using the amine transporter system. Both agents, along with the somatostatin analogue 177Lutetium-DOTATATE, have shown objective response rates in approximately 30% of patients with progressive metastatic disease. Symptomatic improvement is observed in most patients receiving these drugs and evidence of survival benefit is also mounting. Serious side effects are uncommon.

PMID: 19635228 [PubMed - indexed for MEDLINE]

Toumpanakis C, Garland J, Marelli L, Srirajaskanthan R, Soh J, Davies P, Buscombe J, Caplin ME.
Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK.

Alimentary Pharmacology & Therapeutics Journal. 2009 Oct;30(7):733-40. Epub 2009 Jul 2.

Background: Octreotide LAR is an established treatment for malignant carcinoid syndrome. However, studies with large number of patients and long follow-up are lacking. AIM: To present long-terms results with octreotide LAR, assessing duration of clinical and objective response and treatment tolerance, in a large, homogeneous cohort of patients with malignant carcinoid syndrome.

Methods: A total of 108 patients with metastatic midgut neuroendocrine tumours were included in this 8-year study. Clinical evaluation was based on a symptom score. Radiological assessment was based on RECIST (Response Evaluation Criteria In Solid Tumours) criteria.

Results: Of the 108 patients, 24% had a sustained symptomatic response. In the remaining patients, loss of symptomatic response with the initial dose was noted within 3-60 months. In 17% of them, symptoms were controlled by just an increase of octreotide LAR dose, whilst the other patients required additional treatment. Overall, in 45.3% of patients, symptoms were well controlled during the study period with only octreotide LAR, and no additional treatment was required. No significant adverse effects were noted.

Conclusions: Octreotide LAR treatment provides a sustained symptomatic response in about half of the patients with malignant carcinoid syndrome and contributes to disease stabilization for a longer period than previously described.

PMID: 19573169 [PubMed - in process]

http://www3.interscience.wiley.com/journal/122484106/abstract

Vinik AI, Silva MP, Woltering EA, Go VL, Warner R, Caplin M.
Eastern Virginia Medical School, Strelitz Diabetes Research Center,  Norfolk, VA 23510, USA.

vinikai@evms.edu

Pancreas. 2009 Nov;38(8):876-89.

Abstract: In this review, we focus on the use of biochemical markers for the diagnosis of neuroendocrine tumors and exclusion of conditions that masquerade as neuroendocrine tumors. In addition, we outline the use of biochemical markers for follow-up, response to intervention, and determination of prognosis. Previous publications have focused only on markers specific to certain tumor types, but the uniqueness of this chapter is that it presents a new approach ranging from biochemical markers that relate to symptoms to the use of markers that facilitate decision making with regard to optimizing the choices of therapy from the complex arrays of intervention, The sequence of presentation in this chapter is first to provide the usual view, that is, biochemical markers of each tumor type and thereafter the diagnosis of the underlying condition or exclusion thereof and finally the algorithm for their use from the clinical presentation to the suspected diagnosis and the biochemical markers to monitor progression and therapeutic choice. There is also a specific description of the properties of the most important biochemical markers and 2 complications, bone metastasis and carcinoid heart disease, from the biochemical point of view.

PMID: 19855234 [PubMed - in process]

http://journals.lww.com/pancreasjournal/pages/currenttoc.aspx

Anja Rinke, Hans-Helge Müller, Carmen Schade-Brittinger, Klaus-Jochen Klose, Peter Barth, Matthias Wied, Christina Mayer, Behnaz Aminossadati, Ulrich-Frank Pape, Michael Bläker, Jan Harder, Christian Arnold, Thomas Gress, and Rudolf Arnold

Journal of Clinical Oncology. 2009 Oct 1;27(28):4656-63.

Conclusion: Octreotide LAR significantly lengthens time to tumor progression compared with placebo in patients with functionally active and inactive metastatic midgut NETs.

Comprehensive description of neuroendocrine tumors: symptoms, diagnosis and treatment. Presented here with permission from Dr. Demeure.
Michael J. Demeure, MD, MBA
Senior Investigator
Endocrine & Cancer Surgery
Scottsdale, AZ
Tel:480-323-1570

Swärd C, Johanson V, Nieveen van Dijkum E, Jansson S, Nilsson O, Wängberg B, Ahlman H, Kölby L on May 2009 in British Journal of Surgery

Conclusion: Hepatic Arery Embolization is safe, provides good control of hormonal symptoms, and prolongs survival in biochemically responsive patients. It is a valuable palliative option for patients with midgut carcinoid syndrome due to liver metastases and can be repeated in patients with a favourable response to the first procedure. Copyright (c) 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

PMID: 19358175 [PubMed - as supplied by publisher] read full text

Priorities for Improving the Management of Gastroenteropancreatic Neuroendocrine Tumors

Irvin M. Modlin , Steven F. Moss , Daniel C. Chung , Robert T . Jensen , Elizabeth Snyderwine

Published by: J Natl Cancer Inst 2008;100: 1282 – 1289 Vol. 100, Issue 18 | September 17, 2008

Abstract: A National Cancer Institute summit meeting on gastroenteropancreatic neuroendocrine and carcinoid tumors was held in September 2007 to present the currently accepted standards of care for patients with these tumors and to identify areas requiring investigation and development. These tumors are clinically and pathologically heterogeneous, present commonly with obscure symptoms that lead to delays in diagnosis of years, and have an incidence in the United States of 2.5 to 5 cases per 100 000. The 5-year survival rates range between 15% and 95%, depending on the site and extent of disease. This report delineates the main conclusions of the meeting, including the best practice diagnosis and treatment strategies for gastropancreatic neuroendocrine tumors, and the identification of clinical and scientific areas that are most in need of attention. The most pressing needs were public and physician education, identification of molecular markers for early diagnosis and therapeutic monitoring, improved imaging modalities and molecular prognostication, development of a standardized pathological classification system, and creation of regional centers of expertise with tumor and laboratory data banks. In addition, adequately validated neuroendocrine tumor models and cell lines should be established to investigate the molecular mechanisms involved in the control of their growth and secretion, and to facilitate the development of specific therapies that should be examined in well-designed multicenter studies of defined patient groups.

Woltering EA, Salvo VA, O'Dorisio TM, Lyons J 3rd, Li G, Zhou Y, Seward JR, Go VL, Vinik AI, Mamikunian P, Mamikunian G.

Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA, USA. ewolte@lsuhsc.edu

Pancreas. 2008 Jul;37(1):94-100. Abstract

Conclusion: Current plasma octreotide values are significantly lower than previously reported for 30-, 60-, and 120-mg/mo LAR doses. Serial plasma octreotide value measurements should be used to determine if increasing symptoms or tumor growth are associated with suboptimal drug dosing.

  • Improving Worldwide Cancer Care and Prevention Awareness

Oncology by OncologyStat
    
OncologySTAT's mission is to improve worldwide cancer care and prevention by providing healthcare professionals with immediate integrated access to the most authoritative evidence-based information available. OncologySTAT’s commitment to international health ensures that news, research, education, and analysis from all regions of the world are covered in a publisher, society, and sponsor-neutral online environment.

TIP: for example, type "carcinoid tumors all sites" (or other cancers) in the advanced search window and you will receive a comprehensive list of up-to-date peer-review articles of carcinoid tumors from over 100 Elsevier cancer-related journals, including The Lancet Oncology, The Breast, Lung Cancer, The American Journal of Medicine, Cancer Letters, etc. Many articles are full text.    

Online Full Text

Yao JC, Eisner MP, Leary C, Dagohoy C, Phan A, Rashid A, Hassan M, Evans DB. Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. jyao@mdanderson.org

Ann Surg Oncol. 2007 Dec;14(12):3492-500. Epub 2007 Sep 26.

Conclusion: Patients with malignant pancreatic neuroendocrine tumors commonly present with advanced disease. Although, curative resection is not frequent, survival benefit may be obtainable with aggressive surgical management even in the face of metastatic disease.

Note: Acknowledgments supported by gifts from Raymond Sackler, the J. Stuart Foundation, and the Carcinoid Cancer Foundation.

J Vasc Interv Radiol. 2007 Jul;18(7):847-55

Ruutiainen AT, Soulen MC, Tuite CM, Clark TW, Mondschein JI, Stavropoulos SW, Trerotola SO.

Division of Interventional Radiology, University of Pennsylvania, 1 Silverstein, Philadelphia, PA 19104, USA

Abstract

Conclusions: Chemoembolization was not associated with a higher degree of toxicity than bland embolization. Chemoembolization demonstrated trends toward improvement in TTP, symptom control, and survival. Based on these results, a multicenter prospective randomized trial is warranted.

Oncologist. 2007 Aug;12(8):942-51

Greenblatt DY, Vaccaro AM, Jaskula-Sztul R, Ning L, Haymart M, Kunnimalaiyaan M, Chen H

F.A.C.S., H4/750 Clinical Science Center, 600 Highland Avenue, Madison, Wisconsin 53792, USA.

Carcinoid tumors are neuroendocrine malignancies that frequently metastasize and secrete hormones that cause debilitating symptoms in patients. In this study we report the effects of valproic acid (VPA), a drug long used for the treatment of epilepsy, on the growth and neuroendocrine phenotype of human carcinoid cancer cells. VPA treatment of gastrointestinal and pulmonary carcinoid cells resulted in a dose-dependent inhibition of cancer cell growth. Western blot analysis revealed degradation of cyclin D1 and an increase in cyclin-dependent kinases p21 and p27 with VPA treatment. Flow cytometry confirmed that the mechanism of VPA-induced growth inhibition is G(1) phase cell cycle arrest. Furthermore, VPA suppressed expression of the neuroendocrine tumor marker chromogranin A. In addition to these effects, VPA also increased levels of full-length Notch-1 and the active Notch-1 intracellular domain. Luciferase reporter assays incorporating the centromere-binding factor 1 (CBF-1) binding site and the achaete-scute complex-like 1 (ASCL-1) promoter confirmed the functional activity of VPA-induced Notch-1. Transfection of Notch-1 small-interfering RNA into carcinoid tumor cells blocked the effects of VPA on Notch-1 activation, ASCL-1 suppression, p21 induction, and cell growth inhibition. VPA also suppressed growth of carcinoid tumors in vivo in a mouse tumor xenograft experiment. These findings confirm the important role of Notch-1 in regulating the growth and neuroendocrine phenotype of carcinoid tumor cells. On the basis of this study, a clinical trial of VPA for patients with advanced carcinoid cancer will be conducted.

Muthusamy Kunnimalayaan, Herbert Chen

Endocrine Surgery Research Laboratories, Department of Surgery, The University of Wisconsin, and the University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin, USA

The Oncologist 2007;12:535–542

Abstract: A growing body of literature is demonstrating that Notch signaling is a more complex process than originally thought. Contradictory findings of notch-1 acting as an oncogene or a tumor suppressor revealed that its role is very specific to the cellular context. In this review we focus on the tumor suppressor role of Notch-1 signaling in neuroendocrine tumors (NETs) such as carcinoid and medullary thyroid cancers. NETs secrete various bioactive hormones that can cause debilitating symptoms. Surgery is the only potential curative treatment for the patients with NETs. Notch-1 signaling is absent in these tumors and activation of Notch-1 significantly reduces tumor growth in vitro. Therefore, identification of compound(s) that activate the Notch-1 pathway in NETs could be a potential strategy to treat patients with NETs.

Liesbeth M Veenendaal1, Inne HM Borel Rinkes1, Cornelis JM Lips2 and Richard van Hillegersberg*1, Netherlands.

Published: 26 June 2006 World Journal of Surgical Oncology 2006, 4:35
Review
Abstract

Background: Neuroendocrine tumours frequently metastasize to the liver. Although generally slowly progressing, hepatic metastases are the major cause of carcinoid syndrome and ultimately lead to liver dysfunction, cardiac insufficiency and finally death.

Conclusion: Treatment for patients with neuroendocrine hepatic metastases must be tailored for each individual patient. When local ablative therapies are used early in the course of the disease, the occurrence of carcinoid syndrome with end stage hepatic disease can be postponed or prevented.

Payam S Pahlavan1  and Rani Kanthan2

1Department of Physiology and Pathophysiology, University of  Heidelberg, Heidelberg, Germany

2Department of Pathology, University of Saskatchewan, Saskatoon, Canada

World Journal of Surgical Oncology 2005, 3:36

Muthusamy Kunnimalaiyaan, Abram M. Vaccaro, Mary A. Ndiaye, and Herbert Chen

Surgery, University of Wisconsin, Madison, WI 53792
Papers In Press, published online ahead of print November 7, 2006

J. Biol. Chem, 10.1074/jbc.M603578200
Accepted on November 7, 2006

Abstract

 Other papers published by Muthusamy Kunnimalaiyaan in Pub Med

What is Cell culture drug resistance testing (CCDRT)?
Also known as "chemotherapy sensitivity and resistance assays" or ("CSRAs")

This journal describes the use of CCDR and its use to identify the best forms of chemotherapy for cancer patients on an individual basis.

Gregg Mamikunian, MS; Aaron I. Vinik, MD, PhD, FCP, MACP; Thomas M. O’Dorisio, MD; Eugene A. Woltering, MD, FACS; Vay Liang W. (Bill) Go, MD

Published by Inter Science Institute, 2009.

This book adds a new dimension to patient diagnosis, management and monitoring, not only through powerfully discriminating assays, but through the recognition of clinical presentations and syndromes.

To print the full text, 259 pages, CLICK HERE.

If you prefer you can order the book or a CD from Inter Science Institute.
For book/CD requests, use this e-mail address:  requests@interscienceinstitute.com.

Norton JA, Fang TD, Jensen RT.

Department of Surgery, Stanford University Medical Center, Room H-3591, 300 Pasteur Drive, Stanford, CA 94305-5641, USA. janorton@stanford.edu

 J Natl Compr Canc Netw. 2006 Feb;4(2):148-53.

Irvin M. Modlin, Igor Latich, Mark Kidd, Michelle Zikusoka, and Geeta Eick. Review

Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8062, USA. imodlin@optonline.net

Clin Gastroenterol Hepatol. 2006 May;4(5):526-47.

Full text

Irvin M. Modlin, Mark Kidd, Igor Latich, Michelle N. Zikusoka, and Michael D. Shapiro

Gastric Pathobiology Research Group, GI Surgical Division, Yale University School of Medicine, New Haven, Connecticut Review

Gastroenterology, May, 2005;128:1717–1751 (Full Text)

Richard R.P. Warner
Gastrointestinal Division, Department of Medicine
The Mount Sinai School of Medicine, New York, NY
Gastroenterology, May 2005;128:1668–1684
(Access Full Text) With permission from the author.

Eugene A. Woltering MD FACS
The James D. Rives Professor of Surgery and Neurosciences
Louisiana State University Health Sciences Center
New Orleans LA 70065
March 2005
(Access full text with permission from the author)
The drug octreotide acetate is part of a class of drugs know as somatostatin analogs (This class of drugs includes octreotide, lanreotide and most recently, vapreotide). All of these drugs can be given subcutaneously (SC), intravenously (pump-based therapy) or by depot injections of a slow release form of the compound (LAR).

Shah GM, Shah RG, Veillette H, Kirkland JB, Pasieka JL, Warner RR.
Am J Gastroenterol. 2005 Oct;100(10):2307-14.
It has been shown that giving niacin supplementation to carcinoid patients not only resolves several common symptoms of carcinoid and pellagra, such as skin lesions and diarrhea/ steatorrhea, but also generally improves the health of the carcinoid patients (10, 12, 29). Therefore, our results warrant that niacin status should be determined for all carcinoid patients, so that active niacin replacement could be provided to biochemically niacin-deficient patients. In areas of the world where preformed niacin is not added to the food supply and screening of niacin status is not possible, all carcinoid patients should be supplemented with niacin as a preventative therapy.
(Full Text) with permission from the authors

Johann M. Zeutenhorst, Babs G. Taal
Oncologist. 2005 Feb;10(2):123-31
Free Full Text Article online

  • Special Book Edition

Current Status of the Diagnosis and Treatment of Hereditary and Sporadic Neuroendocrine Tumors of the Gastroenteropancreatic System (Free abstracts)
European Neuroendocrine Tumor Society (ENETS), Budapest, March 2004
Neuroendocrinology 80 (suppl) 1 1-140(2004)
Editor B Wiedenmann, Publisher Karger
Access Author and Subject Index
Order information
Pictures from the Budapest conference

Up-to-the-minute CME, in the form of lively, practice-oriented discussions between leading specialists, brought to you by the American Gastroenterological Association (AGA).

Topical CME from leading experts
Neuroendocrine tumors: Timely diagnosis and optimal intervention
Chaired by Lowell Anthony MD
Faculty: Thomas O’Dorisio MD; Richard Warner MD
This program has been specifically developed to update and educate gastroenterologists and primary care physicians who provide care for people with NET

This website, created by Endotext.org. provides comprehensive, authoritative, and updated full text information on endocrine disease directed to physicians around the world caring for patients with these problems. All material may be freely downloaded for personal use and is a textbook format.

Topics covered on these webpages included:

          o Introduction-Development and Anatomy, by Aaron Vinik,               M.D.,  Ph.D.
          o Carcinoid Tumors, by Aaron Vinik M.D.
          o Gastrinoma Syndrome, by Roger R Perry, M.D. , FACS
          o Insulinomas, by Roger R Perry M.D.
          o MEN I and MEN I, by Roger R Perry M.D.
          o VIPomas, by Aaron Vinik M.D.
          o Glucagonoma, by Aaron Vinik M.D.
          o Somatostatinoma, by Aaron Vinik M.D.
          o Pancreatic Polypeptide-oma, by Aaron Vinik M.D.
          o Neurotensinoma, by Aaron Vinik M.D.
          o Ghrelinoma, by Aaron Vinik M.D.
          o Management of Neuroendocrine Tumors of the GI Tract, by               Aaron Vinik M.D.
          o Chemotherapy for Islet Cell Carcinomas, by Aaron Vinik M.D.

This link is to an abstract. Full text of this volume is available to subscribers of the Annals of the New York Academy of Sciences or by per-article payment. Nonmembers may browse the table of contents and abstracts by following the link above.
Volume 1014 published April 2004
Edited by Bertram Wiedenmann; Gerhard M. Christofori; Michael Hoecker

"Chromogranin A is an important general tumor marker for all types of carcinoid tumors. Somatostatin receptor scintigraphy is a cornerstone in staging and localization of carcinoid tumors, but newer techniques such as positron emission tomography will challenge its position in the future. Although surgical cure is not obtainable, a more aggressive surgery has emerged during the last decade. Debulking and other cytoreductive procedures are quite common today. Somatostatin analogues have been the treatment of choice in symptomatic patients with carcinoid tumors, but more recent studies have indicated a cytostatic effect of somatostatin analogues. Tumor-targeted radioactive treatment based on somatostatin analogues is now under clinical evaluation. Preliminary data indicate interesting clinical potentials."

Incidence/Statistics

CONCLUSIONS: Carcinoids appear to have increased in overall incidence over the past 30 years; for some sites, this trend has been evident for nearly half a century. Recent marked increases in gastric and rectal carcinoids and a concomitant decrease in appendiceal carcinoid incidence may be due in part to varying rules of registration among the compiled databases examined in this report or to improvements in diagnostic technology; increased awareness of and about carcinoid tumors also may play a significant role. In 12.9% of all patients with carcinoid, distant metastases already were evident at the time of diagnosis; the overall 5-year survival rate for all carcinoid tumors, regardless of site, was 67.2%. These findings bring into question the widely promulgated relative benignity of carcinoid disease. Certain carcinoid tumors, such as those of the rectum, appear to be over-represented among the black and Asian populations within the United States, suggesting the role of genetics in the development of this intriguing disease.

Carcinoid Heart Disease

CONCLUSIONS: High levels of 5-HIAA excretion and ANP were found to be associated with CHD.
"...there was an even stronger relationship between carcinoid heart disease and the serotonin load over time."
"Even in the absence of severe symptoms of the carcinoid syndrome, it is highly recommended that serotonin levels be reduced." "Which can be realized by combination of different treatment modalities such as octreotide analogues,......" and other treatment modalities.

This link is to an abstract. Full text is available at www.heartjnl.com to subscribers of Heart or by per-article payment
Fox DJ, Khattar RS.
Heart. 2004 Oct;90(10):1224-8

Review:

Tricuspid and pulmonary valve regurgitation usually occurs as a secondary phenomenon caused by dilatation of the valve ring secondary to right ventricular failure or pulmonary hypertension, respectively. Primary diseases of the tricuspid or pulmonary valves are uncommon, but the more likely causes might include congenital abnormalities, rheumatic heart disease, or infective endocarditis. Carcinoid heart disease is a rare, but interesting and important cause of intrinsic tricuspid and pulmonary valve disease leading to significant morbidity and mortality caused by right heart failure. When treated medically, and in appropriate cases surgically, significant benefits in overall quality of life and long term survival can be achieved. We review the current literature regarding the pathophysiological basis of the disease, the cardiovascular complications, and the currently available treatment strategie.

Clinical trials

  • Results from Clinical Trials of Systemic treatment with Y90, LU-177 and 111-In

Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs (Full Text)
Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S, Kvols LK, O'dorisio TM, Valkema R, Bodei L, Chinol M, Maecke HR, Krenning EP.
J Nucl Med. 2005 Jan;46 Suppl 1:62S-6S.

Conclusion: The results obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the duration of the therapy response for both radiopharmaceuticals is more than 2 y. These data compare favorably with those for the limited number of alternative treatment approaches.

Other Topics of Interest

Pediatric Carcinoid

  • Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions. (Abstract)
    J Pediatr Gastroenterol Nutr. 2005 Feb;40(2):216-9
    Dall'Igna P, Ferrari A, Luzzatto C, Bisogno G, Casanova M, Alaggio R, Terenziani M, Cecchetto G.
    "Although rare, carcinoid tumor of the appendix is the most common neoplasm of the gastrointestinal tract in children and adolescents. It is usually an incidental finding after a laparotomy for appendectomy, with a frequency of 2 to 5 cases per 1000 appendectomies. The experience with 14 cases of carcinoid reported in the appendix is described."

Bronchial/Lung Carcinoid

  • Bronchial Carcinoid
    By Dan Granberg M.D. : Bronchial Carcinoids.
    Uppsala, 2001. - 75p.
    Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,
    ISSN 0282-7476 ; 1006
    ISBN 91-554-4957-3

Granberg D, Skogseid B.
In: Doherty G, Skogseid B, eds. Surgical Endocrinology. Philadelphia. Lippincott Williams & Wilkins. 2001:413-430

Granberg D, Eriksson B, Wilander E, Grimfjärd P, Fjällskog M-L, Öberg K, Skogseid B. Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol 2001;12(10):1383-1391

Ekeblad S, Eriksson B, Sundin A, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Örlefors H, Sigurd M, Öberg K, Janson ET, Skogseid B
Clin Cancer Res 2007;13(10):2986-2991

 

van Essen M, Krenning EP, Bakker WH, de Herder WW, van Aken MO, Kwekkeboom DJ. Eur J Nucl Med Mol Imaging 2007;34(8):1219-1227

Guigay J.
Poster presented at the12th World Conference on Lung Cancer, Seoul, Korea, September 2007.

 

  

Genetics

 

Wang GG, Yao JC, Worah S, White JA, Luna R, Wu TT, Hamilton SR, Rashid A.
Mod Pathol. 2005 Aug;18(8):1079-87.
PMID: 15920555 [PubMed - indexed for MEDLINE]
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
"Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. . . . Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles."